Kegg Pathway: Alzheimer's disease

J Neurosci Res. 2008 Jul 21;
Borg J, Chereul E

Clinical magnetic resonance imaging (MRI) offers a noninvasive diagnostic tool for neurodegenerative diseases. MRI was performed on mice to investigate a relationship between brain atrophy and overexpression of two genes involved in such diseases, SOD1 (superoxide dismutase) and APP (amyloid precursor protein), which have been associated with pathogenesis of Alzheimer's disease or Down syndrome. Additionaly, we investigated how life span and growth rate were affected by genetic background. T2-weighted MRI made possible the measurement of the volume of brain regions of interest in living transgenic mice that overexpress normal APP, SOD1, or both. The most pronounced alterations in gray matter volume were observed in 1-year-old double APP/SOD1 transgenic mice. Hippocampus, entorhinal, and cingulate cortex volumes were decreased by 8% to 25%. In contrast, mice homozygous for SOD1 exhibited atrophy specifically in cortex regions (cingulate, retrosplenial, and temporoparietal cortex), but no significant modification was found in the hippocampus region. None of these alterations was seen in single APP transgenics. However, the life span of these mice was significantly shortened. SOD1 overexpression prevented APP toxicity with regard to premature death, especially in double APP/SOD1 transgenic animals homozygous for SOD1, and increase in life span was significantly correlated to SOD1 activity. In conclusion, overexpression of both APP and SOD1, in contrast to single APP transgenics, produced a robust effect on brain anatomy but did not impair growth or life span. Consequences of genotype alterations on brain atrophy may be dissociated from their effect on life span. (c) 2008 Wiley-Liss, Inc.

Cochrane Database Syst Rev. 2008; CD002854
Isaac MG, Quinn R, Tabet N

BACKGROUND: Vitamin E is a dietary compound that functions as an antioxidant scavenging toxic free radicals. Evidence that free radicals may contribute to the pathological processes of cognitive impairment including Alzheimer's disease (AD) has led to interest in the use of Vitamin E in the treatment of Alzheimer's disease and Mild Cognitivie Impairment (MCI). OBJECTIVES: To assess the efficacy of Vitamin E in the treatment of Alzheimer's disease and prevention of progression of Mild Cognitive Impairment to Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement's Specialized Register was searched on 8 January 2007 using the following terms: "Vitamin E", vitamin-E, alpha-tocopherol. The CDCIG Registers contains records from major health care databases and ongoing trial databases and is updated regularly. SELECTION CRITERIA: All unconfounded, double blind, randomized trials in which treatment with Vitamin E at any dose was compared with placebo for patients with Alzheimer's disease or Mild Cognitive Impairment. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the selection criteria and assessed study quality and extracted and analysed the data. For each outcome measure data were sought on every patient randomized. Where such data were not available an analysis of patients who completed treatment was conducted. MAIN RESULTS: Only 2 studies met the inclusion criteria. The primary outcome used in the AD study was survival time to the first of 4 endpoints: death, institutionalisation, loss of 2 out of 3 basic activities of daily living and severe dementia (defined as a global Clinical Dementia Rating of 3). The investigators reported the total numbers in each group who reached the primary endpoint within two years for participants completing the study ("completers"). There appeared to be some benefit from Vitamin E with fewer participants reaching endpoint - 58% (45/77) of completers compared with 74% (58/78) - a Peto odds ratio of 0.49, 95% confidence interval 0.25 to 0.96.However, more participants taking Vitamin E suffered a fall (12/77 compared with 4/78; odds ratio 3.07, 95% CI 1.09 to 8.62). It was not possible to interpret the reported results for specific endpoints or for secondary outcomes of cognition, dependence, behavioural disturbance and activities of daily living.The primary outcome used in the MCI study which had 769 participants (257 in the Vitamin E group and 259 in the placebo group; a third Donepezil group of 253 was not included in this review) was the time to progression from MCI to possible or probable AD. A total of 214 of the 769 participants had progression to dementia, with 212 being classified as having possible or probable AD. There was no significant difference in the probability of progression from MCI to AD between the Vitamin E group and the placebo group. There was no significant difference between the placebo group and the Vitamin E group in adverse events. Five subjects died in each group and 72 discontinued treatment in the Vitamin E group and 66 in the placebo group. AUTHORS' CONCLUSIONS: There is no evidence of efficacy of Vitamin E in the prevention or treatment of people with AD or MCI. More research is needed to identify the role of Vitamin E, if any, in the management of cognitive impairment.

PPAR Res. 2008; 2008: 403896
Kummer MP, Heneka MT

Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.

Neuroscience. 2008 Jul 1;
Napoli I, Neumann H

Microglial cells are of hematopoietic origin, populate the CNS during early development and form the brain's innate immune cell type. Besides their well-known role in immune defense, microglia have an active and homeostatic function in the normal CNS based on high motility of their ramified processes and endocytic clearance of apoptotic vesicular material. During development microglia contribute to the reorganization of neuronal connections, however microglia have also pivotal roles during acute and chronic neurodegeneration. Microglia become attracted to site of injury by nucleotides released from damaged neurons. Scavenger receptors expressed on microglia bind to debris and microglial phagocytic receptors signal via immunoreceptor tyrosine-based activation motif (ITAM) -containing adaptor proteins to promote phagocytosis of extracellular material. Insufficient clearance by microglia appears to be prevalent in neurodegenerative diseases such as Alzheimer disease.

Eur J Pharmacol. 2008 Jul 5;
Qu HY, Zhang T, Li XL, Zhou JP, Zhao BQ, Li Q, Sun MJ

Alzheimer's disease is a progressive brain disorder with the loss of memory and other intellectual abilities. Amyloid species and neurofibrillary tangles are the prime suspects in damaging and killing nerve cells. Abnormal accumulation of Amyloid-beta peptide (Abeta) may cause synaptic dysfunction and degeneration of neurons. Drugs that can prevent its formation and accumulation or stimulate its clearance might ultimately be of therapeutic benefit. Ciliary neurotrophic factor (CNTF), a neurotrophic cytokine, promotes the survival of various neurons in brain. However, the blood-brain barrier hinders the systemic delivery of CNTF to brain. Recently the 11-amino acid of protein transduction domain TAT has successfully assisted the delivery of many macromolecules to treat preclinical models of human disease. The present study aimed to evaluate whether P11-CNTF fusion protein (P11-CNTF) is protective against the Abeta25-35-induced dementia in mice. Immunofluorescence experiments showed that P11 effectively carried CNTF to the SH-SY5Y cells in vitro, and to the brains of mice in vivo. The learning and memory impairments of mice induced by Abeta were substantially rescued by supplement with the P11-CNTF. Furthermore, mRNAs of enzymes involved in the Abeta metabolism, e.g. neprilysin (NEP), endothelin-converting enzyme 1 (ECE-1) and insulin degrading enzyme (IDE), increased in the P11-CNTF treated dementia mice, accompanied by the proliferation of nestin- and choline acetyltransferase (ChAT)-positive cells in hippocampus. It implies that the delivery of P11-CNTF may be a novel treatment for Alzheimer's disease.

BMC Neurol. 2008 Jul 21; 8(1): 27
Tobinick EL, Gross H

ABSTRACT: BACKGROUND: Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease. METHODS: This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25-50 mg, weekly by perispinal administration for six months. Two additional case studies are presented. RESULTS: Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p=.05. The FAS test for letter fluency was most highly significant with a p<0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented. CONCLUSIONS: In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these results further argue that larger scale studies of this therapeutic intervention, including Phase 3 trials, are warranted in dementias. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying Alzheimer's disease and related forms of dementia, and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in Alzheimer's disease which are worthy of further investigation.

J Neurochem. 2008 Jul 17;
Wang Y, Zhang JX, Du XX, Zhao L, Tian Q, Zhu LQ, Wang SH, Wang JZ

We have reported that activation of glycogen synthase kinase-3 (GSK-3) by ventricle injection of wortmannin (WT) and GF-109203X (GFX) induces Alzheimer-like memory deficit in rats (Liu et al., J Neurochem. 2003). To further explore the factors responsible for the memory loss, we studied here the temporal alterations of GSK-3, tau phosphorylation, beta-amyloid (Abeta) and acetylcholine after injection of WT/GFX, and analyzed their correlation with the memory loss. We observed that the severe memory deficit occurred at 24 h and 48 h, and simultaneously, GSK-3 activation, tau hyperphosphorylation at Thr231, Ser396 and Ser404 and decline of acetylcholine in hippocampus were detected, and these changes were mostly recovered at 72 h and 96 h after the injection of WT/GFX. Remarkable increase of Abeta and intracellular accumulation of argentophilic substances were detected at 72 h. Pearson analysis showed that the memory deficit was correlated with GSK-3 activation, tau hyperphosphorylation and decline of acetylcholine but not with Abeta overproduction. Our data provide direct evidence demonstrating that activation of GSK-3 by WT/GFX may cause memory deficit through tau hyperphosphorylation and suppression of acetylcholine in hippocampus.

Int J Urol. 2008 Jul 17;
Sakakibara R, Uchiyama T, Yamanishi T, Kishi M

Urinary incontinence is common in patients with dementia, and is more prevalent in demented than in non-demented older individuals. Neurogenic incontinence is common in multiple cerebral infarction and dementia with Lewy bodies, and in both diseases walking difficulty and falls are common. In contrast, functional incontinence is common in Alzheimer's disease due to cognitive disability and decreased motivation. Central cholinergic stimulation is the mainstay in the treatment of cognitive decline. In contrast, to date, the use of anticholinergic medications for detrusor overactivity in the elderly is still under consideration, since anticholinergic drugs may lead to undesirable events particularly in the central nervous system, although many studies have used severely demented cases. In the future, studies seeking treatment regimens for an elderly individual with both dementia and urinary dysfunction are warranted.

J Neurochem. 2008 Jul 15;
McTigue DM, Tripathi RB

Oligodendrocytes are mature glial cells that myelinate axons in the brain and spinal cord. As such, they are integral to functional and efficient neuronal signaling. The embryonic lineage and post-natal development of oligodendrocytes have been well-studied and many features of the process have been described, including the origin, migration, proliferation and differentiation of precursor cells. Less clear is the extent to which oligodendrocytes and damaged/dysfunctional myelin are replaced following injury to the adult central nervous system (CNS). Oligodendrocytes and their precursors are very vulnerable to conditions common to CNS injury and disease sites, such as inflammation, oxidative stress and elevated glutamate levels leading to excitotoxicity. Thus, these cells become dysfunctional or die in multiple pathologies, including Alzheimer's disease, spinal cord injury, Parkinson's disease, ischemia and hypoxia. However, studies of certain conditions to date have detected spontaneous oligodendrocyte replacement. This review will summarize current information on adult oligodendrocyte progenitors, mechanisms that contribute to oligodendrocyte death, the consequences of their loss and the pathological conditions in which spontaneous oligodendrogenesis from endogenous precursors has been observed in the adult CNS.

Phys Rev E Stat Nonlin Soft Matter Phys. 2008 Jun; 77(6 Pt 1): 061921
Xie Y, Chen L, Kang YM, Aihara K

It is a challenging problem to establish safe and simple therapeutic methods for various complicated diseases of the nervous system, particularly dynamical diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease. From the viewpoint of nonlinear dynamical systems, a dynamical disease can be considered to be caused by a bifurcation induced by a change in the values of one or more regulating parameter. Therefore, the theory of bifurcation control may have potential applications in the diagnosis and therapy of dynamical diseases. In this study, we employ a washout filter-aided dynamic feedback controller to control the onset of Hopf bifurcation in the Hodgkin-Huxley (HH) model. Specifically, by the control scheme, we can move the Hopf bifurcation to a desired point irrespective of whether the corresponding steady state is stable or unstable. In other words, we are able to advance or delay the Hopf bifurcation, so as to prevent it from occurring in a certain range of the externally applied current. Moreover, we can control the criticality of the bifurcation and regulate the oscillation amplitude of the bifurcated limit cycle. In the controller, there are only two terms: the linear term and the nonlinear cubic term. We show that while the former determines the location of the Hopf bifurcation, the latter regulates the criticality of the Hopf bifurcation. According to the conditions of the occurrence of Hopf bifurcation and the bifurcation stability coefficient, we can analytically deduce the linear term and the nonlinear cubic term, respectively. In addition, we also show that mixed-mode oscillations (MMOs), featuring slow action potential generation, which are frequently observed in both experiments and models of chemical and biological systems, appear in the controlled HH model. It is well known that slow firing rates in single neuron models could be achieved only by type-I neurons. However, the controlled HH model is still classified as a type-II neuron, as is the original HH model. We explain that the occurrence of MMOs can be related to the presence of the canard explosion where a small oscillation grows through a sequence of canard cycles to a relaxation oscillation as the control parameter moves through an interval of exponentially small width.

Arq Neuropsiquiatr. 2008 Jun; 66(2b): 436-443
Guimarães HC, Levy R, Teixeira AL, Beato RG, Caramelli P

Apathy is considered the most frequent neuropsychiatric disturbance in dementia and its outcome is generally deleterious. Apathy can be related to a dysfunction of the anatomical-system that supports the generation of voluntary actions, namely the prefrontal cortex and/or the prefrontal-subcortical circuits. In Alzheimer's disease, pathological and neuroimaging data indicate that apathy is likely due to a dysfunction of the medial prefrontal cortex. Accordingly, in this review article, we propose a pathophysiological model to explain apathetic behavior in Alzheimer's disease, combining data from neuroimaging, neuropathology and experimental research on the role of orbito-frontal cortex, anterior cingulate cortex, basal ganglia and dopamine in decision-making neurobiology.

Arq Neuropsiquiatr. 2008 Jun; 66(2b): 323-327
Arcoverde C, Deslandes A, Rangel A, Rangel A, Pavão R, Nigri F, Engelhardt E, Laks J

BACKGROUND: The practice of physical activities has proved to be an efficient strategy in the improvement of independency and cognitive functions in the elderly with Alzheimer's disease (AD). OBJECTIVE: To evaluate the relation between the practice of physical activity, cognition and activities of daily living (ADL) of patients with AD. METHOD: The cognitive and physical aspects and ADL were evaluated of 37 elders (19 normal controls, 11 sedentary with AD and 7 active with AD). RESULTS: The variable that best predicts the cognitive state (MMSE) is the duration of disease for the AD sedentary group and Lawton's Scale for the AD active group. We observed a correlation between MMSE score and duration of disease in the sedentary group and between MMSE and ADL in the active group. CONCLUSION: Our study showed that physical and cognitive stimulation in patients with AD can contribute to decrease cognitive and functional decline.

Arq Neuropsiquiatr. 2008 Jun; 66(2b): 318-322
Martins SP, Damasceno BP

OBJECTIVE: To study prospective and retrospective memory in patients with mild Alzheimer's disease (AD). METHOD: Twenty mild AD and 20 matched normal control subjects were included. Diagnosis of AD was based on DSM-IV and NINCDS-ADRDA criteria, using CDR 1 and MMSE scores from 16 to 24 for mild AD. All subjects underwent retrospective (Rey Auditory Verbal Learning Test, RAVLT) and prospective memory tests (the appointment and belonging subtests of the Rivermead Behavioral Memory Test, RBMT; and two tests made to this study: the clock and the animals test), as well as MMSE, neuropsychological counterproofs, and Cornell Scale for Depression in Dementia. The data was analyzed with Wilcoxon test and Spearman correlation coefficient. RESULTS: AD patients performed worse than controls in prospective and retrospective memory tests, with poorer performance in retrospective memory. There was no correlation between prospective memory and attention, visual perception, executive function, or depression scores. CONCLUSION: Prospective and, in higher degree, retrospective memory are primarily and independently impaired in mild AD.

Arq Neuropsiquiatr. 2008 Jun; 66(2b): 298-302
Garcia AN, Silva HA, Silva RC, Leal EM, Rodrigues L, Silva VC, Dellalibera E, Freitas EM, Ataíde Jr L, Muniz MT

BACKGROUND: Polymorphism of the gene for apolipoprotein E (APOE) is an important risk factor for the development of Alzheimer's disease. The epsilon4 allele of the APOE gene has been linked with a number of neuropsychiatric illnesses, and also with stress and depression among geriatric populations. OBJECTIVE: To identify APOE-epsilon4 polymorphism and correlate this with cognitive deficit among the elderly population of the island of Fernando de Noronha. METHOD: Neuropsychiatric tests (mini-mental state examination, verbal fluency test and clock drawing test) were applied to 52 elderly people without Alzheimer's disease. DNA was isolated from peripheral blood and genotyping of APOE was done by the PCR-RFLP method. RESULTS: 87% of the elderly population (mean age 69.6+/-7.0) had cognitive deficit. CONCLUSION: The observed frequency of the epsilon4 allele was 10%, but the correlation between the presence of epsilon4 and cognitive deficit in this population was not statistically significant.

J Nutr. 2008 Aug; 138(8): 1578S-1583S
Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MB

Green tea is currently considered a source of dietary constituents endowed with biological and pharmacological activities relevant to human health. Human epidemiological and new animal data suggest that the pharmacological benefits of tea drinking may help to protect the brain as we age. Indeed, tea consumption is inversely correlated with the incidence of dementia and Alzheimer's and Parkinson's diseases. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. The intense efforts dedicated in recent years to shed light on the molecular mechanisms participating in the brain protective action of green tea indicate that in addition to the known antioxidant activity of catechins, the modulation of signal transduction pathways, cell survival/death genes, and mitochondrial function all contribute significantly to the induction of neuron viability. Because of the multietiological character of neurodegenerative disease pathology, these natural compounds are receiving significant attention as therapeutic cytoprotective agents that simultaneously manipulate multiple desired targets in the central nervous system. This article elaborates on the multimodal activities of green tea polyphenols with emphasis on their recently described neurorescue/neuroregenerative and mitochondrial stabilization actions.

Hum Mol Genet. 2008 Jul 17;
Rodríguez-Navarro JA, Gómez A, Rodal I, Perucho J, Martinez A, Furió V, Ampuero I, Casarejos MJ, Solano RM, García de Yébenes J, Mena MA

Deposition of proteins leading to amyloid takes place in some neurodegenerative diseases such as Alzheimeŕs disease and Huntingtońs disease. Mutations of tau and parkin proteins produce neurofibrillary abnormalities without deposition of amyloid. Here we report that mature, parkin null, over-expressing human mutated tau (PK(-/-)/Tau(VLW)) mice have altered behavior and dopamine neurotransmission, tau pathology in brain and amyloid deposition in brain and peripheral organs. PK(-/-)/Tau(VLW) mice have abnormal behavior and severe drop out of dopamine neurons in the ventral midbrain, up to 70 %, at 12 months and abundant phosphorylated tau positive neuritic plaques, neuro-fibrillary tangles, astrogliosis, microgliosis, and plaques of murine beta-amyloid in the the hippocampus. PK(-/-)/Tau(VLW) mice have organomegaly of the liver, spleen and kidneys. The electron microscopy of the liver confirmed the presence of a fibrillary protein deposits with amyloid characteristics. There is also accumulation of mouse tau in hepatocytes. These mice have lower levels of CHIP-HSP70, involved in the proteosomal degradation of tau, increased oxidative stress, measured as depletion of glutathione which, added to lack of parkin, could trigger tau accumulation and amyloidogenesis. This model is the first that demonstrates beta-amyloid deposits caused by over-expression of tau and without modification of the amyloid precursor protein, presenilins or secretases. PK(-/-)/Tau(VLW) mice provide a link between the two proteins more important for the pathogenesis of Alzheimer disease.

Bioorg Med Chem. 2008 Jul 8;
León R, Ríos CD, Marco-Contelles J, Huertas O, Barril X, Javier Luque F, López MG, García AG, Villarroya M

In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1,8]naphthyridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca(2+)] elevation elicited by K(+) depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer's disease.

Lancet. 2008 Jul 19; 372(9634): 216-23
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA

BACKGROUND: Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes. METHODS: In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Abeta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Abeta immunostaining (Abeta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model. FINDINGS: 20 participants--15 in the AN1792 group, five in the placebo group--died before follow-up started. A further 22 patients--19 in the AN1792 group, three in the placebo group--died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Abeta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in Abeta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group. INTERPRETATION: Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.

Lancet. 2008 Jul 19; 372(9634): 207-15
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D,

BACKGROUND: Although treatments for Alzheimer's disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimer's disease. METHODS: We enrolled 183 patients with mild-to-moderate Alzheimer's disease (mini-mental state examination [MMSE] scores 10-24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. FINDINGS: 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference -4.0 [95% CI -5.73 to -2.28]; p<0.0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference -1.9 [-2.92 to -0.85]; p=0.0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. INTERPRETATION: Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease.

Lancet. 2008 Jul 19; 372(9634): 180-2
St George-Hyslop PH, Morris JC